14 research outputs found
Use of 3D Properties to Characterize Beyond Rule-of-5 Property Space for Passive Permeation
The application of conformationally dependent measures
of size
and polarity to characterize beyond rule-of-5 (Ro5) space for passive
permeation was investigated. Specifically, radius of gyration, an
alternative to molecular weight, and three-dimensional polar surface
area and the generalized Born/surface area dehydration free energy,
alternatives to hydrogen-bond donor and acceptor counts, were computed
on models of the permeating conformations of over 35 000 molecules.
The resulting guidelines for size and polarity, described by the 3D
properties, should aid the design of Ro5 violators with passive permeability
Biaryl-Bridged Macrocyclic Peptides: Conformational Constraint via Carbogenic Fusion of Natural Amino Acid Side Chains
A general method for constraining peptide conformations
via linkage of aromatic sidechains has been developed. Macrocyclization
of suitably functionalized tri-, tetra- and pentapeptides via Suzuki–Miyaura
cross-coupling has been used to generate side chain to side chain,
biaryl-bridged 14- to 21-membered macrocyclic peptides. Biaryl bridges
possessing three different configurations, meta–meta, meta–ortho,
and ortho–meta, were systematically explored through regiochemical
variation of the aryl halide and aryl boronate coupling partners,
allowing fine-tuning of the resultant macrocycle conformation. Suzuki–Miyaura
macrocyclizations were successfully achieved both in solution and
on solid phase for all three sizes of peptide. This approach constitutes
a means of constraining peptide conformation via direct carbogenic
fusion of side chains of naturally occurring amino acids such as phenylalanine
and tyrosine, and so is complementary to strategies involving non-natural,
for example, hydrocarbon, bridges
Exploring Aromatic Chemical Space with NEAT: Novel and Electronically Equivalent Aromatic Template
In this paper, we describe a lead transformation tool,
NEAT (<u>N</u>ovel and <u>E</u>lectronically
equivalent <u>A</u>romatic <u>T</u>emplate), which can
help identify novel aromatic rings that are estimated to have similar
electrostatic potentials, dipoles, and hydrogen bonding capabilities
to a query template; hence, they may offer similar bioactivity profiles.
In this work, we built a comprehensive heteroaryl database, and precalculated
high-level quantum mechanical (QM) properties, including electrostatic
potential charges, hydrogen bonding ability, dipole moments, chemical
reactivity, and othe properties. NEAT bioisosteric similarities are
based on the electrostatic potential surface calculated by Brood,
using the precalculated QM ESP charges and other QM properties. Compared
with existing commercial lead transformation software, (1) NEAT is
the only one that covers the comprehensive heteroaryl chemical space,
and (2) NEAT offers a better characterization of novel aryl cores
by using high-evel QM properties that are relevant to molecular interactions.
NEAT provides unique value to medicinal chemists quickly exploring
the largely uncharted aromatic chemical space, and one successful
example of its application is discussed herein
Exploring Aromatic Chemical Space with NEAT: Novel and Electronically Equivalent Aromatic Template
In this paper, we describe a lead transformation tool,
NEAT (<u>N</u>ovel and <u>E</u>lectronically
equivalent <u>A</u>romatic <u>T</u>emplate), which can
help identify novel aromatic rings that are estimated to have similar
electrostatic potentials, dipoles, and hydrogen bonding capabilities
to a query template; hence, they may offer similar bioactivity profiles.
In this work, we built a comprehensive heteroaryl database, and precalculated
high-level quantum mechanical (QM) properties, including electrostatic
potential charges, hydrogen bonding ability, dipole moments, chemical
reactivity, and othe properties. NEAT bioisosteric similarities are
based on the electrostatic potential surface calculated by Brood,
using the precalculated QM ESP charges and other QM properties. Compared
with existing commercial lead transformation software, (1) NEAT is
the only one that covers the comprehensive heteroaryl chemical space,
and (2) NEAT offers a better characterization of novel aryl cores
by using high-evel QM properties that are relevant to molecular interactions.
NEAT provides unique value to medicinal chemists quickly exploring
the largely uncharted aromatic chemical space, and one successful
example of its application is discussed herein
Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules
Macrocyclic peptides are considered
large enough to inhibit “undruggable” targets, but the
design of passively cell-permeable molecules in this space remains
a challenge due to the poorly understood role of molecular size on
passive membrane permeability. Using split-pool combinatorial synthesis,
we constructed a library of cyclic, per-N-methlyated peptides spanning
a wide range of calculated lipohilicities (0 < <i>A</i>log<i>P</i> < 8) and molecular weights (∼800
Da < MW < ∼1200 Da). Analysis by the parallel artificial
membrane permeability assay revealed a steep drop-off in apparent
passive permeability with increasing size in stark disagreement with
current permeation models. This observation, corroborated by a set
of natural products, helps define criteria for achieving permeability
in larger molecular size regimes and suggests an operational cutoff,
beyond which passive permeability is constrained by a sharply increasing
penalty on membrane permeation
Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules
Macrocyclic peptides are considered
large enough to inhibit “undruggable” targets, but the
design of passively cell-permeable molecules in this space remains
a challenge due to the poorly understood role of molecular size on
passive membrane permeability. Using split-pool combinatorial synthesis,
we constructed a library of cyclic, per-N-methlyated peptides spanning
a wide range of calculated lipohilicities (0 < <i>A</i>log<i>P</i> < 8) and molecular weights (∼800
Da < MW < ∼1200 Da). Analysis by the parallel artificial
membrane permeability assay revealed a steep drop-off in apparent
passive permeability with increasing size in stark disagreement with
current permeation models. This observation, corroborated by a set
of natural products, helps define criteria for achieving permeability
in larger molecular size regimes and suggests an operational cutoff,
beyond which passive permeability is constrained by a sharply increasing
penalty on membrane permeation
Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products
Cyclic peptide natural products contain
a variety of conserved,
nonproteinogenic structural elements such as d-amino acids
and amide N-methylation. In addition, many cyclic peptides incorporate
γ-amino acids and other elements derived from polyketide synthases.
We hypothesized that the position and orientation of these extended
backbone elements impact the ADME properties of these hybrid molecules,
especially their ability to cross cell membranes and avoid metabolic
degradation. Here we report the synthesis of cyclic hexapeptide diastereomers
containing γ-amino acids (e.g., statines) and systematically
investigate their structure–permeability relationships. These
compounds were much more water-soluble and, in many cases, were both
more membrane permeable and more stable to liver microsomes than a
similar non-statine-containing derivative. Permeability correlated
well with the extent of intramolecular hydrogen bonding observed in
the solution structures determined in the low-dielectric solvent CDCl<sub>3</sub>, and one compound showed an oral bioavailability of 21% in
rat. Thus, the incorporation of γ-amino acids offers a route
to increase backbone diversity and improve ADME properties in cyclic
peptide scaffolds
Un incontro internazionale sugli effetti dell'innalzamento del livello marino
Cyclic constraints are incorporated
into an 11-residue analogue
of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate
effects of structure on agonist activity. Cyclization through linking
side chains of residues 2 and 5 or 5 and 9 produced agonists at nM
concentrations in a cAMP assay. 2D NMR and CD spectra revealed an
N-terminal β-turn and a C-terminal helix that differentially
influenced affinity and agonist potency. These structures can inform
development of small molecule agonists of the GLP-1 receptor to treat
type 2 diabetes
Peptide to Peptoid Substitutions Increase Cell Permeability in Cyclic Hexapeptides
The effect of peptide-to-peptoid
substitutions on the passive membrane
permeability of an <i>N</i>-methylated cyclic hexapeptide
is examined. In general, substitutions maintained permeability but
increased conformational heterogeneity. Diversification with nonproteinogenic
side chains increased permeability up to 3-fold. Additionally, the
conformational impact of peptoid substitutions within a β-turn
are explored. Based on these results, the strategic incorporation
of peptoid residues into cyclic peptides can maintain or improve cell
permeability, while increasing access to diverse side-chain functionality
Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes
Acetyl-CoA
carboxylase (ACC) inhibitors offer significant potential
for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis,
and cancer. However, the identification of tool compounds suitable
to test the hypothesis in human trials has been challenging. An advanced
series of spirocyclic ketone-containing ACC inhibitors recently reported
by Pfizer were metabolized in vivo by ketone reduction, which complicated
human pharmacology projections. We disclose that this metabolic reduction
can be greatly attenuated through introduction of steric hindrance
adjacent to the ketone carbonyl. Incorporation of weakly basic functionality
improved solubility and led to the identification of <b>9</b> as a clinical candidate for the treatment of T2DM. Phase I clinical
studies demonstrated dose-proportional increases in exposure, single-dose
inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry
consistent with increased whole-body fatty acid oxidation. This demonstration
of target engagement validates the use of compound <b>9</b> to
evaluate the role of DNL in human disease